Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction

The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (6a–6c) were synthesized as antitumor agents. Compounds6aand6cexhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly,6aeffectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of6aand6c, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that6aand6carrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition,6aand6ccaused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca2+release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that6aand6cexerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.Keywords:dithiocarbamate;ruthenium polypyridyl complexes;antitumor activity;DNA damage;cell cycle arrest;apoptosis